Disruption of histidine and energy homeostasis in chronic obstructive pulmonary disease

Abstract

Background

Chronic obstructive pulmonary disease (COPD) is a systemic condition that is too complex to be assessed by lung function alone. Metabolomics has the potential to help understand the mechanistic underpinnings that contribute to COPD pathogenesis. Since blood metabolomics may be affected by sex and body mass index (BMI), the aim of this study was to determine the metabolomic variability in male smokers with and without COPD who have a narrow BMI range.

Methods

We compared the quantitative proton nuclear magnetic resonance acquired serum metabolomics of a male Chinese Han population of non-smokers without COPD, and smokers with and without COPD. We also assessed the impact of smoking status on metabolite concentrations and the associations between metabolite concentrations and inflammatory markers such as serum interleukin-6 and histamine, and blood cell differential (%). Metabolomics data were log-transformed and auto-scaled for parametric statistical analysis. Mean normalized metabolite concentration values and continuous demographic variables were compared by Student’s t-test with Welch correction or ANOVA with post-hoc Tukey’s test, as applicable; t-test p-values for metabolomics data were corrected for false discovery rate (FDR). A Pearson association matrix was built to evaluate the relationship between metabolite concentrations, clinical parameters and markers of inflammation.

Results

Twenty-eight metabolites were identified and quantified. Creatine, glycine, histidine, and threonine concentrations were reduced in COPD patients compared to non-COPD smokers (FDR ≤15%). Concentrations of these metabolites were inversely correlated with interleukin-6 levels. COPD patients had overall dampening of metabolite concentrations including energy-related metabolic pathways such as creatine metabolism. They also had higher histamine levels and percent basophils compared to smokers without COPD.

Conclusion

COPD is associated with alterations in the serum metabolome, including a disruption in the histidine-histamine and creatine metabolic pathways. These findings support the use of metabolomics to understand the pathogenic mechanisms involved in COPD.

Trial registration www.clinicaltrials.gov, NCT3310177.

Keywords:

• China
• metabolomics
• histidine
• energy homeostasis
• inflammation
• chronic obstructive pulmonary disease

Acknowledgments

The present study was funded by the National Natural Science Foundation of China (Grant Nos: 81270097; 81470235; 81670034) and Beijing Medical University (Grant Nos: 20110176; 20160529) and the University of Michigan Health System-Peking University Health Science Center Joint Institute for Translational and Clinical Research. K. Stringer’s contribution was supported in part by a grant from the National Institutes of Health (NIH), National Institute of General Medical Sciences (NIGMS; GM111400). M. Han and W. Labaki’s contribution was supported by a grant from the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health (K24 HL138188). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIGMS, NHLBI, or the National Institutes of Health.

Abbreviations

COPD, chronic obstructive pulmonary disease; BMI, body mass index; NMR, nuclear magnetic resonance; FDR, false discovery rate; HRCT, high resolution computed tomography; LAA, low attenuation area; GOLD, global Initiative for chronic obstructive lung disease; NCS, non-COPD smokers; NS, Never smokers; FEV1, forced expiratory volume in the first second; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6.

Ethics approval and consent to participate

The study (www.clinicaltrials.gov, NCT3310177) was approved by the Peking University (PUIRB) and the University of Michigan Institutional Review Boards (IRBMed). Written informed consent was acquired from all subjects before enrollment into the study in accordance with the principles of the Declaration of Helsinki.

Data sharing statement

The dataset supporting the conclusions of this article is available in the NIH Metabolomics Workbench repository (http://www.metabolomicsworkbench.org/).

Author contributions

W Diao directed the execution of the study, participated in the assaying of the metabolomics samples, conducted bioinformatic and statistical analyses and interpretation and wrote the manuscript; W Labaki, assisted with data analysis and interpretation and the writing of the manuscript; M Han, T Standiford, B He, N Shen and K Stringer were involved in study design; P Xiang, N Shen, Y Sun, C Guo and M Lu enrolled subjects; L Yeomans, Z Smiley, Y Sun, J Kim and C McHugh performed the metabolomics assays, free haemoglobin assays, NMR spectral analyses and generated the metabolomics data set; C Guo measured IL-6, TNF-alpha and fibrinogen levels. All authors contributed to data analysis, drafting and revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

Dr MeiLan Han reports personal fees from BI, GSK, AZ and research support from Novartis and Sunovion, outside of the submitted work. The authors report no other conflicts of interest in this work.